토끼 VX2 간종양 모델을 이용한 전임상 연구

학위논문(박사) -- 서울대학교대학원 : 의과대학 의학과, 2021.8. 정진욱.Introduction: Transarterial chemoembolization (TACE) is an image-guided locoregional therapy used for the treatment of patients with primary or secondary liver cancer. However, conventional TACE formulations are rapidly dissociated due to the instability of the emulsion, resulting in insufficient local drug concentrations in the target tumor. The aim of this study was to prove the feasibility of albumin-doxorubicin nanoparticle conjugated microbubble (ADMB) for enhancing therapeutic efficiency by sonoporation under exposure to ultrasound, and to develop a novel drug delivery system composed of doxorubicin-loaded albumin nanoparticles-conjugated microbubble complex in iodized oil emulsion (DOX-NPs-MB complex in Lipiodol) to overcome these limitations and to evaluate safety and therapeutic efficacy of ultrasound-triggered TACE using this formulation. Materials and methods: This study was comprised of two parts; the first part was for fabrication and evaluation of in-vitro characteristics of ADMB, including size distribution, drug release profile, and echogenicity. Therapeutic efficacy was assessed using rabbit VX2 tumor model. The second part was for development and in-vivo validation of DOX-NPs-MB complex in iodized oil emulsion as a new ultrasound-triggered TACE formulation. Results: ADMB demonstrated a size distribution of 2.33 ± 1.34 µm and a doxorubicin loading efficiency of 82.7%. The echogenicity of ADMBs was sufficiently generated in the 2–9 MHz frequency range and cavitation depended on the strength of the irradiating ultrasound. DOX-NPs-MB constituting the complex retained their function as an ultrasound contrast agent in Lipiodol. In the in vivo study, ultrasound-triggered TACE using DOX-NPs-MB complex in Lipiodol formulation (US+) showed a lower viable tumor portion than the conventional TACE formulation, and effectively killed cancer cells in the peripheral region of the tumor. Liver toxicity was comparable to that of conventional therapies. Conclusion: In summary, by introducing a doxorubicin-loaded microbubble in the TACE formulation, it was possible to improve both drug delivery to the tumor with real-time monitoring, and therapeutic efficacy of TACE. This enhanced TACE formulation may provide a new means of treating liver cancer.서론: 경동맥화학색전술 (Transarterial chemoembolization; TACE)는 간암의 국소 치료에서 중요한 위치를 차지하고 있는 치료법이다. 그러나 고식적인 TACE는 주입한 에멀젼이 불안정하여 혈액 내에서 빠르게 분리되면서 국소 약물 전달 효과는 떨어지고 전신 부작용이 생기는 문제점이 있다. 본 연구는, 이와 같은 TACE의 한계를 극복하기 위한 초음파 감응형 항암제 함유 알부민 나노입자-마이크로버블 복합체와, 이 복합체와 요오드화 기름과의 새로운 에멀젼을 개발하여 약물전달능 및 종양살상능을 향상시키는 새로운 초음파 감응형 간동맥화학색전술용 에멀젼을 개발하는 것이다. 방법: 이 연구는 크게 2 단계로 구분되어 있다. 먼저 항암제 함유 나노입자-마이크로버블 복합체 (Albumin nanoparticle-Doxorubicin conjugated Microbubble; ADMB) 를 제작하고 물리화학적 특성 을 분석하였다. In-vivo study를 위하여 토끼 VX2 간종양 모델을 이용하였다. 최종적으로 개발된 ADMB와 iodized oil과의 에멀젼을 이용하여 in-vitro characteristics 및in-vivo therapeutic efficacy 와 safety를 검증하였다. 결과: ADMB는 약 2.33 ± 1.34 µm 의 크기를 가지며 doxorubicin loading efficiency는 82.7%였다. ADMB는 2–9 MHz 주파수 범위에서 가시적인 초음파 조영능을 보였으며 방사하는 초음파 세기에 따라 cavitation 효과를 보였다. 토끼 간종양 모델을 이용한 실험에서 ADMB군은 치료를 하지 않은 대조군에 비해 약 5배의 종양 성장 억제 효과를 보였다. DOX-NPs-MB 에멀젼 역시 ADMB와 유사한 정도의 초음파 조영능을 보였고 in-vivo 실험에서 새로 개발된 DOX-NPs-MB 에멀젼을 외부 초음파와 감응시키면서 종양에 주입하였을 때, 기존 에멀젼보다 유의하게 높은 종양 살상능을 보였고 간독성에는 두 군간 차이가 없었다. 결론: 새로 개발된 외부 초음파 감응형 DOX-NPs-MB 에멀젼은 기존의 고식적인 에멀젼보다 약물 전달능, 종양 살상능이 우수하였으며 초음파로 실시간 약물 전달 모니터링이 가능하였다. 이 새 에멀젼은TACE에서 간암 치료 효과를 높일 수 있는 새로운 수단이 될 것으로 기대된다.Abstract 3 Introduction 8 Materials and Methods 10 Results 23 Discussion 47 Conclusion 54 References 57박

뇌동맥류내 코일색전술 실패 후 수술을 통한 코일 제거 및 뇌동맥류 결찰

Despite modern advances in endovascular techniques, intraaneurysmal coil embolization may be associated with serious complications such as parent artery occlusion by thromboembolism and coil migration or incomplete treatment, which require surgery. We report 5 cases in which surgical interventions had been necessary following coil embolization with Guglielmi Detachable Coil, either due to incomplete aneurysm obliteration or acute complication of parent artery occlusion by coil migration and throm-boembolism. Surgical intervention include removal of the coils and clipping of the aneurysm. Immediate recanalization of the occluded artery by use of intra-arterial thrombolytics and surgery is very important. The role of neurosurgical management in the care of the patients suffering from unsuccessful endovascular therapy of aneurysm is demonstrated.ope

Management of elderly patients with intracranial aneurysm

Objectives : A clinical analysis was performed to provide management strategy and to improve management outcome of elderly patients with intracranial aneurysm. Patients and Methods : We reviewed medical records of 746 consecutive patients with intracranial aneurysm who were admitted from July 1991 to December 1996. They were divided into two age groups : elderly(120 patients aged 65 years or older) and non-elderly(626 patients aged 64 years or younger). We investigated the differences between the two groups in clinical characteristics, management outcome and surgical results. Results : Female(80.0%), internal carotid artery aneurysm(48.9%), poor clinical grade(Hunt and Hess Grade IV, V : 39.8%), postoperative subdural fluid collection(38.2%), and postoperative hydrocephalus(39.7%) were more frequent in the elderly patients. There were no significant differences in the incidence of hypertension, multiple aneurysm, unruptured aneurysm, rebleeding, delayed ischemic neurological deficits, postoperative hemorrhage, and low density on the postoperative brain CT scan. In some cases, surgical clipping of ruptured aneurysm could not be performed due to moribund state or refusal of surgery by the elderly patient's family. Both management outcome and surgical results in elderly aneurysm patients at 3 months after rupture were worse than those of the non-elderly group. The most common reason of unfavorable outcome was poor clinical grade in both groups, while serious medical illness causing unfavorable outcome was more common in the elderly group. Conclusion : Surgical treatment of a ruptured aneurysm should not be avoided in elderly patient solely on the basis of advanced age. If the patients are in good clinical grade, early aneurysm surgery followed by early ambulation should be recommended. Further improvements in outcome may be achieved by thorough knowledge of poor resilience of brain, CSF flow dynamics, and diminished cardiopulmonary reserve in elderly patients with intracranial aneurysm.ope

A Newly-Developed Flow Diverter (FloWise) for Internal Carotid Artery Aneurysm: Results of a Pilot Clinical Study

OBJECTIVE: We report the results of a pilot clinical study that evaluated the safety and efficacy of a newly-developed, retrievable flow diverter (FloWise; Taewoong Medical) for the treatment of internal carotid artery (ICA) aneurysm. MATERIALS AND METHODS: A total of 10 patients were enrolled. Inclusion criteria were 1) unruptured aneurysm with a dome size of ≥ 8 mm and a neck size of ≥ 4 mm at the ICA, or 2) two or more unruptured aneurysms of any size able to be spanned by a single FloWise at the ICA. Co-primary effectiveness end points were technical success of FloWise placement, and a 50% or greater decrease in aneurysm volume at the 6-month follow-up angiogram. The primary safety end point was the new development of neurological deficits persisting for more than 1-month post-treatment. RESULTS: Ten patients harboring 14 ICA aneurysms (median diameter, 9.4 mm; range, 2.3-31.0 mm) were enrolled between January 2016 and July 2017. FloWise placement was successful in all patients. There were no newly-developed neurological deficits during the 6-month clinical follow-up period. One patient did not receive follow-up imaging due to pregnancy. Nine patients with 12 aneurysms received a 6-month angiographic follow-up. Ten aneurysms (83.3%) showed decreases in volume greater than 50% (mean volume decrease, 82.8 ± 32.9%), of which 8 (66.7%, 95% confidence interval, 35.4-98.0%) showed complete occlusion. One patient was retreated due to mass symptom aggravation. CONCLUSIONS: In this pilot study, FloWise appeared to be safe and effective for ICA aneurysm treatment. A prospective multicenter study to validate the effectiveness and safety of FloWise would be worthwhile.ope

A Clinical Experience of 72 Patients with Aneurysms arising from the Anomalous Cerebral Artery

Objective : Aneurysm rupture at the anomalous artery is rare but inadvertent clip occlusion may cause critical complications. The aim of this study was to examine the frequency of the cerebral aneurysms associate with the vascular anomalies and the surgical considerations. Methods : We analyzed 2802 patients with aneurysms treated from September, 1976 to July, 2004. A diagnosis of 'anomalous artery ' was made on the basis of angiographic or surgical findings in 72 patients. Surgery was carried out in 68 patients and 4 were treated with endovascular methods. Results : Fenestrated anterior communicating artery (A-com.) was the most common anomaly (33cases, 45. 8%), 24 cases of 3rd A2 (33.3%), and 9 cases of azygous A2 (12.5%). fenestrated M1 was 1 cases (1.4%) and the one duplicated MCA (1. 4%). 3 cases of fenestrated basilar artery (4.2%) and one primitive trigeminal artery aneurysm (1.4%) were treated with GDC. In our series vascular anomalies were found in 6% of the all Acom aneurysm cases. Conclusion : It is often difficult to recognize a fenestration or other anomalies of cerebral arteries prior to surgery, even with precise angiographic analysis. The A-com artery complex is one of most frequent sites of vascular anomalies. Preoperative and intraoperative concerns is required to avoid inadvertent occlusion of parent artery or misplacement of clip, which may result in critical complications or poor outcomes.ope

Risk Factors of Seizures Associated with the Management of Ruptured Cerebral Aneurysms

Objective : This study was designed to to analyze the associated risk factors of seizure after aneurysmal subarachnoid hemorrhage(SAH) for providing guidelines of prophylactic antiepileptic drug administration. Method : We retrospectively reviewed the programmed clinical database and radiographic findings of the patients with aneurysmal SAH who were treated from March 1996 to August 2004 and followed up for more than one year. Result : A total of 512 patients were enrolled. 20 patients (3.9%) presented with seizures. Aneurysm location and size were not associated with seizures. The incidence of seizure was significantly different in the Hunt & Hess Grade IV patients (8.6%) and V patients (23.1%). Fisher Grade IV was associated with a significantly higher risk of the seizure (12.2%). The incidence of seizure was higher in patients with hydrocephalus (6.7%), intracerebral hematoma (8.8%), and decompressive lobectomy (14.3%). Conclusion : The overall incidence of seizures was 3.9%. Risk factors of seizures were poor clinical grade (Hunt &Hess Grade IV and V), higher Fisher Grade (IV), hydrocephalus, intracerebral hematoma, and decompressive lobectomy.ope

MR-DWI–Positive Lesions and Symptomatic Ischemic Complications After Coiling of Unruptured Intracranial Aneurysms

BACKGROUND AND PURPOSE: The aims of this study are to evaluate the risk factors for symptomatic ischemic complication (symptomatic ischemic complication [SIC], transient ischemic attack, or stroke) and microembolisms detected as MR diffusion-weighted imaging (MR-DWI)-positive (DWI(+)) lesions, and the relationship between DWI(+) and SIC after coiling of unruptured intracranial aneurysm. METHODS: Between March 2009 and November 2011, 382 unruptured intracranial aneurysms in 343 patients underwent both coiling and posttreatment MR-DWI. The incidence of and risk factors for SIC and DWI(+), and the relationship between DWI(+) and SIC were retrospectively analyzed. RESULTS: The incidence of SIC was 4.1%. The incidence of DWI(+) was 54.5%. The number of DWI(+) lesions was significantly larger in the SIC group, than in the asymptomatic one (12.1±10.4 versus 5.0±8.7, P<0.00). The cutoff value of DWI(+) for predicting SIC was ≥6 (sensitivity 85.7%, specificity 70.7%). The patients with DWI(+) ≥6 was 28.6%. Of the patients with SIC, the patients with DWI(+) ≥6 was 78.6%. Patients aged≥65 years had a trend for SIC, and it was the only independent risk factor for DWI(+) ≥cutoff (n=6; 95%CI, 1.167-3.083). CONCLUSIONS: The number of DWI(+) lesions was significantly larger in the SIC group than in the asymptomatic one after coiling of unruptured intracranial aneurysm. Patients aged≥65 had a trend for SIC, and it was the only independent risk factor for the number of DWI(+) ≥cutoff value (n=6) for predicting SIC.ope

Specific Characteristics and Management Strategies of Posterior Cerebral Artery Aneurysms

Objective：This study was to define clinical characteristics and formulate the management strategies of the patients with posterior cerebral artery (PCA) aneurysms. Patients and Method：The authors reviewed the database and imaging studies as sources for identification and analysis. During the past 14 years, 16 consecutive patients with PCA aneurysms were treated either by surgery or neurointervention. Results：Ten patients had ruptured PCA aneurysms：4 patients were Hunt and Hess Grade I, 1 Grade II, 4 Grade III, and 1 Grade IV. Six patients had unruptured PCA aneurysms：one patient was Grade 1, and the other patient was Grade IV due to ruptured multiple aneurysms. Seven aneurysms were small, 9 (56.2%) were large or giant. Thirteen aneurysms were saccular, 2 were fusiform, and 1 was serpentine. Seven of the 16 patients (43.7%) had multiple aneurysms. Pterional (8) or subtemporal (5) approach was done in 13 patients. The obliteration methods of the aneurysms were neck clipping in 10 patients, and trapping in 3 patients. Endovascular treatment was performed in 3 patients. Five patients showed transient oculomotor nerve palsy and contralateral hemiparesis after the surgery. Persisting oculomotor nerve palsy occurred in one patient. All patients showed favorable outcome (food recovery 14, moderate disability 2). Conclusions：As a result, PCA aneurysms were characterized by high frequency of non - saccular shape, large or giant size with mass effect, and multiple aneurysms. Surgical treatment was necessary for large or giant aneurysm of the distal PCA to decompress midbrain. Wrapping and clipping technique were useful for treatment of fusiform aneurysms. Although ultimate management outcome of the patients with PCA aneurysms were better than the patients with aneurysms of the other location, intra-aneurysmal treatment with Guglielmi detachable coil would be useful for the proximal PCA aneurysms to avoid surgical injury of the P1 perforator or the oculomotor nerve.ope

Clinical Analysis of Microsurgery for Brainstem Cavernous Malformations: Surgical Indications, Optimal Approaches, and Clinical Outcomes

OBJECTIVE: This study aimed to analyze patients who underwent microsurgery for brainstem cavernous malformations (BCMs) and to investigate the effectiveness and the limitations of surgical resection of BCMs. METHODS: We retrospectively analyzed the clinical data of patients who underwent surgical resections for BCMs between 1989 and 2010. We investigated the age distribution, preoperative hemorrhagic rates, initial clinical presentations, locations of the lesions, and preoperative and postoperative Karnofsky Performance Scale (KPS) scores. We also analyzed surgical indications, the timing of surgery, and surgical approaches. RESULTS: All 15 patients underwent microsurgery for BCMs; 13 underwent total resection of their lesions, but 2 underwent incomplete resections and consequently experienced postoperative recurrent hemorrhage. We observed 11 patients through a complete follow-up, for a mean of 53.1 months (range 1-131 months) after diagnosis (nine patients > 24 months follow-up). During the follow-up periods, 3 patients were lost to follow-up, and one patient expired, due to aspiration pneumonia, 31 months postoperatively. The mean preoperative KPS score was 50, and the mean postoperative KPS score was 67. During the complete follow-up period, 3 patients recovered completely (KPS scores of 90-100) and 7 patients (63.6%) showed improvement in KPS scores. CONCLUSIONS: Surgeons should consider microsurgery for BCMs the treatment of choice for patients who suffer from progressive neurological decline. Successful resection of BCMs depends on an optimal surgical approach, appropriate timing of surgery, and well-informed surgical techniques. The aim of surgery must be total resection of the lesions without any deteriorative neurological morbidity.ope

Effect of intra-arterial papaverine infusion on the symptomatic cerebral vasospasm after aneurysmal subarachnoid hemorrhage

Objective：To clarify the benefits and therapeutic effects of intra-arterial papaverine infusion on the symptomatic cerebral vasospasm, we analyzed the results of treatment in 32 patients retrospectively. Methods：A total of 510 patients underwent surgical clipping or endovascular intra-aneurysmal treatment for ruptured intracranial aneurysm between May, 1996 and June, 1999. The delayed ischemic deficit(DID) was developed in 90 of 510 patients. Of these 90 patients, 32 developed symptomatic vasospasm inspite of using modest "3H therapy". The brain CT scan was taken before the intra-arterial infusion of papaverine. The 32 patients underwent 42 intra-arterial papaverine infusion. The symptomatic vasospasm was divided into three groups：deterioration of mental status(Group 1), appearance of a focal neurologic deficit(Group 2), or both(Group 3). We measured Glasgow Coma Scale(GCS), arterial diameters, and cerebral circulation time(CCT) at the time of pre- and postangioplasty. Results：The number of patients in group 1, 2 and 3 were 26, 7, 9 respectively. Eighteen cases showed improvement of GCS more than 2 scores, 16 more than 1, and 8 showed no change of GCS. Average cerebral circulation time(CCT) was decreased ranging from 0.0-67.5%, and arterial diameters were increased in 21 cases ranging from 1 to 4 folds. Conclusion：Intra-arterial papaverine infusion seemed to have therapeutic effects on symptomatic vasospasm by improving the neurological signs and increasing the arterial diameter. We suggest that intra-arterial papaverine infusion would be an useful adjunctive therapeutic modality in symptomatic vasospasm.ope